Drug addiction is a behavioral pathology associated with impairments at excitatory synapses in the nucleus accumbens. The continuing premise of this proposal is that it is possible to pharmacologically repair this impairment(s) and thereby ameliorate the vulnerability to relapse. The possibility that enduring drug-induced changes in accumbens excitatory synapses can be biomarkers for drug addiction has attracted substantial experimental attention over the last 15 years. However, although the behavioral criteria defining drug dependence are shared, including an enduring vulnerability to relapse, many enduring neuroadaptations are not recapitulated between different chemical classes addictive drug. We have explored an approach that drug- induced cellular neuroadaptations shared in common between distinct classes of addictive drug, but not sucrose, may be strong candidate pathologies underpinning the shared behavioral symptoms of addiction. During the previous funding period we and others demonstrated that a shared characteristic between cocaine, heroin, nicotine and alcohol, but not sucrose, is the down-regulation of glial glutamate transport in the core of the nucleus accumbens (NAcore). We also recently discovered that the resulting spillover of synaptic glutamate during reinstated drug seeking initiates transient long-term potentiation (t-LTP) at glutamatergic synapses in NAcore, and this process is regulated by activating matrix metalloprotease-9 (MMP-9) in heroin, cocaine- and nicotine-, but not sucrose-trained rats. MMP-9 is an inducible metalloproteinase that degrades the extracellular matrix (ECM) and thereby signals synaptic plasticity at glutamatergic synapses, such as changes in spine morphology and amplitude of AMPA- mediated currents. The primary experimental goals in continuing this project are to identify the signaling and pathophysiological mechanisms in NAcore that link synaptic glutamate spillover and activating MMP-9 to the subsequent t-LTP that is necessary for reinstating drug seeking. To support the possibility that this sequence of cellula events is a mediator of relapse, we will determine if the signaling mechanisms are shared by animals trained to self-administer heroin and cocaine, but not sucrose.